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Annals of General Psychiatry
Open Access
Primary research
Voxel-based structural magnetic resonance imaging (MRI) study of
patients with early onset schizophrenia
Yujiro Yoshihara
1
, Genichi Sugihara
2
, Hideo Matsumoto
3
, John Suckling
4
,
Katsuhiko Nishimura
1
, Takao Toyoda
1
, Haruo Isoda
5
, Kenji J Tsuchiya
2
,
Kiyokazu Takebayashi
1
, Katsuaki Suzuki
2
, Harumi Sakahara

Abstract
Background: Investigation into the whole brain morphology of early onset schizophrenia (EOS)
to date has been sparse. We studied the regional brain volumes in EOS patients, and the
correlations between regional volume measures and symptom severity.
Methods: A total of 18 EOS patients (onset under 16 years) and 18 controls matched for age,
gender, parental socioeconomic status, and height were examined. Voxel-based morphometric
analysis using the Brain Analysis Morphological Mapping (BAMM) software package was employed
to explore alterations of the regional grey (GM) and white matter (WM) volumes in EOS patients.
Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS).
Results: EOS patients had significantly reduced GM volume in the left parahippocampal, inferior
frontal, and superior temporal gyri, compared with the controls. They also had less WM volume in
the left posterior limb of the internal capsule and the left inferior longitudinal fasciculus. The
positive symptom score of PANSS (higher values corresponding to more severe symptoms) was
negatively related to GM volume in the bilateral posterior cingulate gyrus. The negative symptom
score was positively correlated with GM volume in the right thalamus. As for the association with
WM volume, the positive symptom score of PANSS was positively related to cerebellar WM
(vermis region), and negatively correlated with WM in the brain stem (pons) and in the bilateral
cerebellum (hemisphere region).
Conclusion: Our findings of regional volume alterations of GM and WM in EOS patients coincide
with those of previous studies of adult onset schizophrenia patients. However, in brain regions that
Published: 22 December 2008
Annals of General Psychiatry 2008, 7:25 doi:10.1186/1744-859X-7-25
Received: 4 October 2008
Accepted: 22 December 2008
This article is available from: http://www.annals-general-psychiatry.com/content/7/1/25
© 2008 Yoshihara et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0
),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Annals of General Psychiatry 2008, 7:25 http://www.annals-general-psychiatry.com/content/7/1/25

an independent sample of EOS patients are in demand.
Previous studies of AOS patients have reported the rela-
tionships between structural brain volume alterations,
and positive and negative symptoms in various brain
regions, such as the superior temporal gyrus [18-20],
insula [21], fusiform gyrus [20], parahippocampal gyrus
[22], basal ganglia [23], and prefrontal gyri [24]. As for
EOS patients, a few studies have investigated the relation-
ships between regional brain changes and the symptom
severity, and the regions found to be related to the symp-
toms in EOS patients, such as the hippocampal [5], occip-
ital, and parietal cortices [25], are not entirely consistent
with the reports on AOS patients.
Brain development in early life is thought to be dynamic,
with the patterns of growth being diverse across different
brain regions [26]. In particular, brain regions that are
inherently linked with the pathology of schizophrenia
may undergo disproportional changes during the vulner-
able period of brain development (that is, the period
before adolescence) [27,28]. In the present study, we con-
ducted voxel-based structural MRI analyses to explore any
pattern of regional brain tissue volume abnormalities,
and to elucidate the relationships between the regional
brain volume and the severity of clinical symptoms in
EOS patients.
Methods
Recruitment of participants
Patients who fulfilled Diagnostic and Statistical Manual of
Mental Disorders, 4th edition (DSM-IV) [29] criteria for
schizophrenia and who had been under the age of 18

assessed with the Positive and Negative Syndrome Scale
(PANSS) [30]. Diagnosis was established with the Struc-
tured Clinical Interview for DSM-IV (SCID) [31]. For
those participants under the age of 16, the interview was
supplemented by the KID SCID [32]. Parental socioeco-
Annals of General Psychiatry 2008, 7:25 http://www.annals-general-psychiatry.com/content/7/1/25
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nomic status was determined according to the Standard
Occupational Classification [33], and handedness was
determined by self-report. Statistical significance was set
at p < 0.05 for clinical comparisons, and for the volume
measures (two-tailed).
MRI acquisition
All participants were scanned with a GE Signa 1.5-T sys-
tem (GE Medical Systems, Milwaukee, WI, USA) at the
Hamamatsu University School of Medicine. A preliminary
localising scan in the coronal plane was used to identify
anterior and posterior commissures, and to prescribe
acquisition of a dual echo fast spin echo dataset in a plane
parallel to the intercommissural line. Contiguous, inter-
leaved proton density- and T2-weighted images, each 3-
mm thick, were obtained to provide whole brain cover-
age. The repetition time (TR) was 4000 ms, and echo
times (TE) were 14 and 84 ms with an 8-echo train length.
The matrix size was 256 × 192 collected from a rectangular
field of view of 24 cm × 18 cm, giving an in-plane resolu-
tion of 0.859 mm. The total acquisition time was 9 min 36
s.
Data analysis

'family-wise error rate', in this case by setting the p value
used such that < 1 false-positive cluster was expected
under the null hypothesis [39]. A cluster of grey or white
matter abnormality was defined as a deficit or an excess
depending on whether the volume was reduced or
increased in the EOS group relative to the control group.
Within the patient group, the relationships between grey
and white matter volume and positive, negative and glo-
bal score (PANSS) were estimated by fitting a regression
model at each intracerebral voxel in standard space for
each tissue class separately.
When the assumptions of the parametric methods are not
guaranteed, the non-parametric methods provide the only
analysis that can be considered valid and exact. As the dis-
tribution of the structural data derived from MRI scans
may violate the assumptions, such as normal distribution,
we thus employed non-parametric methods in this study.
Results
Demographic and clinical characteristics
The EOS and healthy control groups were similar as
regards the distribution of age, sex, ethnicity, social class,
and height (Table 1). All participants were right-handed.
Healthy controls had a significantly (p < 0.001) higher
mean IQ than the patients. In all, 17 EOS patients had
received antipsychotic medication, and 1 EOS patient had
never received antipsychotic medication.
Brain and CSF volumetric measures
Global volumes for the whole brain and each of the three
main tissue classes (grey matter, white matter, and CSF)
are shown in Table 2. In the EOS group, grey matter (GM)

in the right thalamus (Figure 4, Table 4). As for the asso-
ciation with WM volume, the positive symptom score of
PANSS was positively related to cerebellar WM (vermis
region), and negatively correlated with WM in the brain
stem (pons) and in the bilateral cerebellum (hemisphere
region) (Figure 5, Table 4). We found no significant asso-
ciation between regional WM volume change and the neg-
ative symptom score of PANSS.
Discussion
To our knowledge, this is the first voxel-based morphom-
etry study indicating significant relationships between
regional brain volume alterations and clinical symptoms
in EOS patients (that is, with onset under 16 years). We
found a significant GM volume reduction and a signifi-
cant increase of CSF in EOS patients. The EOS patients
had a significant reduction of regional GM in the left para-
hippocampal gyrus, the left inferior frontal gyrus, and the
left superior temporal gyrus. In addition, they had
reduced regional WM in the left posterior limb of the
internal capsule, and in the left inferior longitudinal fas-
ciculus. When the correlations between regional GM vol-
ume and positive symptoms were examined within the
EOS patient group, positive symptoms were found to be
significantly correlated with the reduced GM volume in
the bilateral posterior cingulate gyrus, with the increased
WM volume in the cerebellum (vermis region), and with
the reduced WM volume in the brain stem and the bilat-
eral cerebellum (hemisphere region). We also found a
relationship between the severity of negative symptoms
and the increased GM volume in the right thalamus.

Positive and Negative Syndrome Scale:
Positive score - 13.8 (4.4) -
Negative score - 19.1 (10.0) -
Global score - 31.1 (10.7) -
Values are given as the mean (SD), except for sex and social class.
a
Two-tailed t test;
b
χ
2
test.
EOS, early onset schizophrenia; SD, standard deviation.
Table 2: Global brain volumes
Global brain volumes Control group
a
(n = 18)
EOS group
a
(n = 18)
Group difference
(%)
tp Value
Whole brain (ml) 1,325.7 (106.4) 1,290.0 (47.4) 2.7 (Control > EOS) 1.302 0.205
Grey matter (ml) 657.2 (60.4) 621.3 (29.5) 5.5 (Control > EOS) 2.271 0.032
White matter (ml) 496.5 (46.9) 476.9 (19.7) 3.9 (Control > EOS) 1.638 0.115
CSF (ml) 172.0 (20.3) 191.8 (21.9) 11.5 (EOS > Control) -2.813 0.008
Grey matter/whole brain ratio 0.50 (0.01) 0.48 (0.02) 4.0 (Control > EOS) 2.814 0.009
White matter/whole brain ratio 0.37 (0.01) 0.37 (0.01) 0 1.314 0.199
CSF/whole brain ratio 0.13 (0.02) 0.15 (0.01) 15.4 (EOS > Control) -3.507 0.001
a

EOS, the current findings are similar to those reported by
Sigmundsson et al. [23], who investigated WM volume
changes in AOS patients. In addition, diffusion tensor
imaging (DTI) studies of AOS [46] and EOS [47] patients
have also shown WM abnormalities in similar regions.
Table 3: Grey and white matter regional differences between early onset schizophrenia (EOS) group and control group
Area Brodmann area Talairach coordinate of centroid voxel (mm) Number of voxels in cluster
xyz
Control > EOS in grey matter:
Left parahippocampal gyrus, 34/47/22 -57 2 -4 423
Left inferior frontal gyrus,
Left superior temporal gyrus
Control > EOS in white matter:
Left posterior limb of internal
capsule
-20-8-8 418
Left inferior longitudinal fasciculus
Grey matter regional differences between early onset schizophrenia group (n = 18) and control group (n = 18)Figure 1
Grey matter regional differences between early onset schizophrenia group (n = 18) and control group (n = 18).
Blue regions denote areas of grey matter deficits in the early onset schizophrenia group relative to the control group. The left
side of the figure represents the right side of the brain; the z coordinate for each axial slice in the standard space of Talairach
and Tournoux [38] is given in mm. Cluster-wise probability of type I error: p = 0.001, with less than one false-positive cluster
expected over the whole map.
Annals of General Psychiatry 2008, 7:25 http://www.annals-general-psychiatry.com/content/7/1/25
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Therefore, there is evidence emerging from a variety of
sources to suggest that WM abnormalities are part of the
patterns of brain parenchymal aberration associated with
schizophrenia, although they may be a secondary process.

Negative symptom
Positive correlation
Right thalamus 9 -14 12 224
White matter:
Positive symptom
Positive correlation
Cerebellum (vermis) 8 -48 -12 1,370
Negative correlation
Brain stem (pons) -3 -21 -24 921
Cerebellum (hemisphere)
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aging studies of patients with AOS, such as pharmacolog-
ical functional MRI [50] and positron emission
tomography (PET) studies [51]. Furthermore, additional
evidence from some AOS studies that the posterior cingu-
late gyrus volume reduction is associated with other clini-
cal features, such as poor clinical outcome [52], and the
lack of insight and judgment [53], suggests that neural cir-
cuits involving the posterior cingulate gyrus may have an
important role in the pathophysiology of schizophrenia.
Given that the posterior cingulate is related to processing
of emotionally salient stimuli and spatial attention [54],
our finding that the posterior cingulate gyrus became
prominent in relation to positive symptoms suggests that
this region may be involved in the formation of delusions
Association between positive syndrome scores and grey matter tissue class volume in patients with early onset schizophrenia (n = 18)Figure 3
Association between positive syndrome scores and grey matter tissue class volume in patients with early onset
schizophrenia (n = 18). Blue regions denote areas in which lower grey matter volume is predicted by a higher score on a

lamus. This finding is similar to the results of prior AOS
studies showing a positive correlation between thalamic
volume and the severity of negative symptoms [56-58].
The thalamus is thought to play a role in sensory gating, a
disruption of which has been reported to be involved in
schizophrenia [59,60]. Previous AOS studies have also
reported correlations between the negative symptoms and
structural alterations in other brain regions: namely,
reduced volume in the fusiform gyrus [19], frontal lobe
WM [24,61,62], prefrontal GM [63], cingulate WM and
internal capsule [64], and increased volume in the poste-
rior superior temporal gyrus [65]. However, in our sample
of EOS patients, there were no associations between mor-
phological measures in any of these regions and the sever-
ity score of negative symptoms. It could be that at an early
stage of brain development (that is, in adolescence), the
thalamus, which has reciprocal connectivity with the fron-
tal regions, may be predominantly involved in generating
negative symptoms (that is, cognitive deficits) via dis-
turbed connectivity.
A question may arise as to why no relationships were evi-
dent between the clinical symptoms and the morphologi-
cal measures in the three main brain regions (the frontal,
temporal, and parahippocampal gyri) showing significant
volume reductions in our EOS patients. What is puzzling
is that other regions (that is, the posterior cingulate gyrus
and the thalamus) were found to be associated with the
symptoms in this study. One possible interpretation is
that disturbed neural circuits rather than structural altera-
tions per se may play a role in the formation of symptoms

GM regions) between the groups remained significant. As
a result, the effects of IQ on the findings can be taken as
minimal, especially with respect to the regional brain
changes. Third, the effect of medication was not consid-
ered when regional brain changes were compared
between the case and control groups. Antipsychotic med-
ication can affect regional brain morphology in schizo-
phrenia, particularly in the thalamus [69] and basal
ganglia [70], resulting in increased volumes in these
regions. If physicians tended to administer greater dosages
of antipsychotic medication to combat the negative symp-
toms, then the relationship between increased volume in
the thalamus and the negative symptoms found in this
study would be accounted for by the medication effect.
We performed an analysis in which medication dose was
entered as a covariate, and found that the correlation
between the severity of negative symptoms and the
increase of volume in the thalamus remained significant.
Pathophysiological changes in schizophrenia – including
brain morphological changes – may be drastic, especially
in schizophrenic patients with onset before brain matura-
tion. Therefore, studying schizophrenia patients whose
age of onset is as early as childhood is valuable in clarify-
ing the pathophysiological dynamics of the disorder.
Large-scale longitudinal studies are also needed to eluci-
date brain morphological changes in young populations
with early onset schizophrenia.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions

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